title: Synthesis of 3,6-diazabicyclo[3.1.1]heptanes as novel ligands for neuronal nicotinic acetylcholine receptors.
abstract: Alpha series of novel 3,6-diazabicyclo[3.1.1]heptane derivatives 4a-f was synthesized and their affinity and selectivity towards alpha4beta2 and alpha7 nAChR subtypes were evaluated. The results of the current study revealed a number of compounds (4a, 4b and 4c) having a very high affinity for alpha4beta2 (K(i) at alpha4beta2 ranging from 0.023 to 0.056 nM) versus alpha7 nAChR subtypes; among these compounds, the 3-(6-bromopyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane 4c was found to be the most alpha7alpha4beta2 selective term in receptor binding assays (alpha7alpha4beta2=1295). Moreover, compound 4d also had high affinity for the alpha4beta2 nAChR subtype (K(i)=1.2 nM) with considerably high selectivity (alpha7/alpha4beta2=23300).
authors.affiliation: Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, via F. Muroni 23/A, 07100 Sassari, Italy. muri@uniss.it
authors.forename: Gabriele
authors.initials: G
authors.lastname: Murineddu
authors.forename: Caterina
authors.initials: C
authors.lastname: Murruzzu
authors.forename: Maria M
authors.initials: MM
authors.lastname: Curzu
authors.forename: Giorgio
authors.initials: G
authors.lastname: Chelucci
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gotti
authors.forename: Annalisa
authors.initials: A
authors.lastname: Gaimarri
authors.forename: Laura
authors.initials: L
authors.lastname: Legnani
authors.forename: Lucio
authors.initials: L
authors.lastname: Toma
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Pinna
mesh_terms: D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006536:Heptanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D015394:Molecular Structure; D009538:Nicotine / Q000378:metabolism; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: C534185:3-(6-bromopyridin-3-yl)-3,6-diazabicyclo(3.1.1)heptane; D019086:Bridged Bicyclo Compounds, Heterocyclic; D006536:Heptanes; D008024:Ligands; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine